SM_189b: Calcium / Parathyroid / Bone Basic Flashcards
Describe the functions of Ca
Ca functons
- Regulation of excitable tissues
- Secretion
- Coagulation
- Enzymatic activity
- Signal transduction
- Formation and maintenance of the skeleton
Hypocalcemia results in ___
Hypocalcemia results in increased neuromuscular excitability
Hypercalcemia results in ___, ___, ___, ___, ___, and ___
Hypercalcemia results in dehydration, renal stones, pain, weakness, confusion, and cardiac arrhythmias
Normal serum Ca is ___
Normal serum Ca is 8.5-10.4 mg/dL
- Serum Ca generally fluctuates no more than 0.2 mg/dL in either direction throughout the day
- Tight homeostatic control is a consequence of feedback regulation between Ca and PTH
Calcium and PTH have an ___ effect
Calcium and PTH have an opposing effect
Most serum Ca is ___
Most serum Ca is ionized
- Ionized (50%): mediates biological responses
- Complex with anions (10%): phosphate, citrate
- Protein bound (40%): 90% with albumin, remainder with globulins
Intestinal Ca absorption is promoted by ____ and ____
Intestinal Ca absorption is promoted by facilitated diffusion through the small intestin and Vitamin D dependent transport of Ca and P
Calcium loss through the intestine can result from ____, ____, and ____
Calcium loss through the intestine can result from
- Glucocorticoids: decrease Ca absorption
- Mucosal and biliary secretion
- Steatorrhea, diarrhea, and malabsorption syndromes
Ca absorption is increased by ____
Ca absorption is increased by PTH
(at distal nephron)
Calcium excretion is increased by ____, ____, and ____
Calcium excretion is increased by loop diuretics, dietary protein, and glucocorticoids
Loop diuretics (furosemide, ethacrynic acid)
Thiazide diuretics ____ calcium excretion
Thiazide diuretics decrease calcium excretion
Phosphate excretion is increased by ____ and ____
Phosphate excretion is increased by PTH and FGF-23
___ is major site of Ca storage in the body
Bone is major site of Ca storage in the body
Describe Ca handling in bone
Ca handling in bone
- Bone is major site of Ca storage in body: Ca stored largely in a crystalline form resembling hydroxyapatite
- Stable pool is regulated by cellular activity, affected by hormones, cytokines, growth factors, and drugs
- Exchangeable pool provides buffering and acid-base balance
Describe roles of bone
Roles of bone
- Metabolic: Ca homeostasis, buffering
- Structural: supports body, protects internal organs
- Cell development and maturation: bone marrow is site of hematopoiesis, provides bone cell precursors, and produces cytokines that affect bone
Appendicular bone is ___
Appendicular bone is largely compact cortical bone with some trabecular regions
Axial bone is ____
Axial bone is thin cortex, largely trabecular, and highly connected bony plates
- Contains more marrow and fat
- Trabecular bone has highest activity
Ca is regulated in the ____, ____, and ____
Ca is regulated in the intestine, kidney, and bone
Osteoclasts secrete ____ and ____ to ____
Osteoclasts secrete H+ and proteolytic enzymes to degrade bone
RANKL / TRANCE is a ____ produced by ____
RANKL / TRANCE is a membrane-associated cytokine produced by osteoblasts and other cells
RANKL acts on the ___ receptor on osteoclasts and osteoclast precursors
RANKL acts on the RANKL receptor on osteoclasts and osteoclast precursors
RANKL promotes ____, ____, ____, and ____
RANKL promotes fusion, differentiation, activity, and survival of osteoclasts
Osteoblasts secrete ____, ____, ____, and ____
Osteoblasts secrete collagen, other matrix proteins, growth factors, and cytokines
____ is 90% of the protein of the boen matrix (osteoid)
Collagen is 90% of the protein of the boen matrix (osteoid)
- Osteiod + hydroxyapatite = mineralized matrix
____, ____, and ____ are products used as markers of osteoblastic activity
Osteocalcin, alkaline phosphatase, and collagen peptides cleaved off during synthesis are products used as markers of osteoblastic activity
____, ____, and ____ are osteoblast products that affect osteoclasts
Selected cytokines (IL-6), RANKL, and osteoprotegerin (RANKL antagonist) are osteoblast products that affect osteoclasts
____ are the source of osteoblasts
Pluripotent precursors are the source of osteoblasts
(can also give rise to adipocytes, chondrocytes, and myocytes)
____, ____, and ____ promote osteoblast differentiation and activity
Wnt signaling, insulin-like growth factor 1, and bone morphogenic proteins promote osteoblast differentiation and activity
Osteoblasts become ____ as bone forms around the osteoblasts
Osteoblasts become osteocytes as bone forms around the osteoblasts
Describe osteocytes
Osteocytes
- Comprise 90% of the cells of bone
- Sense mechanical load
- Connect with other cells of bone
- Produce sclerostin (protein) that inhibits wnt signaling and osteoblast differentiation
Sclerostin is produced by ____ and inhibits ____ and ____
Sclerostin is produced by osteocytes and inhibits wnt signaling and osteoblast differentiation
Sclerostin ____ increase bone formation
Sclerostin antagonists increase bone formation
Bone remodeling activity is ____ and involves ____
Bone remodeling activity is continual and involves sequential activity of osteoclasts and osteoblasts
Osteoporosis is ____
Osteoporosis is a systematic condition in which osteoblastic activity cannot keep pace with accelerated osteoclastic activity, resulting in the loss of mineral and matrix and increased susceptibility to fracture
Paget’s disease of bone is ___
Paget’s disease of bone is a disorder in which locally increased osteoclastic activity is followed by increased osteoblastic activity, resulting in abnormal bone
Vitamin D is ___
Vitamin D is a secosteroid produced in the skin by action of UV light on 7-dehydrocholesterol
- Vitamins D2 and D3 have differences in side chain
- Vitamin D2 is produced by plants and fungi
- Vitamin D3 is produced by animals
Vitamin D is converted to ____ in the liver
Vitamin D is converted to 25-(OH)-D in the liver
Final activation step for Vitamin D is ____ and occurs in the ____
Final activation step for Vitamin D is 1-hydroxylation and occurs in the kidney
- Stimulated by PTH
- Stimulated by low serum phosphate
- Tightly feedback regulated
Active metabolite of Vitamin D3 is ____
Active metabolite of Vitamin D3 is 1,25(OH)2D3 (calcitriol)
- Considered a hormone / endocrine because it is synthesized at one site in the body and travels through the bloodstream to target sites
Describe calcitriol actions
Calcitriol actions
- Effects produced through nuclear receptors
- Stimulates intestinal Ca and P absorption -> bone mineralization
- Suppresses PTH secretion
In excess, calcitriol can cause ____ through ____ and ____
In excess, calcitriol can cause hypercalcemia through excess Ca and P absorption and direct actions on osteoblasts to increase RANKL
Describe uses of Vitamin D
Vitamin D uses
- Use related to its effects on Ca and P absorption
- Treatment of nutritional rickets
- Treatment of ricks and osteomalacia due to inadequate 1-hydroxylation of 25-OH-D: Vitamin D resistant rickets, VDRR, renal disease, and hypoparathyroidism
- Adequate Vitamin D is important adjunct to other therapy in patients with osteoporosis
Describe Vitamin D analogues with unique properties
Vitamin D analogues with unique properties
- Alphacalcidol (1alpha-hydroxyvitamin D3): does not require 1-hydroxylation, useful when 1-hydroxylase is deficient
- Paracalcitol: suppresses PTH, minimal effects on intestine, useful for secondary hyperparathyroidism
- Calcipotriol: effective topically, used for psoriasis
Describe PTH
PTH
- 84 amino acid peptide
- Derived from a larger peptide by processing steps in the ER and Golgi
- Normally secreted at least partially in a pulsatile manner
- An analogue, 1-34 PTH (teriparatide), has full activity
Calcium ____ regulates release of PTH via the ____
Calcium negatively regulates release of PTH via the Ca-sensing receptor
Calcimimetics act on the ___ to reduce PTH secretion
Calcimimetics act on the Ca sensing receptor to reduce PTH secretion
Calcitriol and analogs ____ release of PTH
Calcitriol and analogs inhibit release of PTH
Cinacalcet is a ___
Cinacalcet is a calcimimetic
Calcimimetics (Cinacalcet) act by ___ and ___
Calcimimetics (Cinacalcet) act by allosterically activating the CaSR and enhancing the sensitivity of CaSR
- Enhanced sensitivity of CaSR: lowers [Ca] at which PTH is suppressed
Cinacalcet is used to ____
Cinacalcet is used to suppress PTH in hyperparathyroidism or parathyroid carcinoma
- Calcimemtic
- Orally effective, metabolized by CYPs, renal excretion
- Side effects: hypocalcemia, adynamic bone disease
PTH acts through ____ in ____ and ____
PTH acts through GPCRs in bone (osteoblasts and osteocytes) and kidney
- PKA and PKC pathways are stimulated
PTH acts on the kidney to ___, ___, and ___
PTH acts on the kidney to
- Increase Ca absorption
- Decrease phosphate reabsorption
- Stimulate 1alpha-hydroxylation of 25-OH-D to form 1,25-(OH)2D3
PTH effects on the intestine are ____, mediated through the ____
PTH effects on the intestine are indirect, mediated through the increase in 1,25-(OH)2D3
Bone ___ results from continuous exposure to PTH
Bone resorption results from continuous exposure to PTH
- Resorption is largely due to increased RANKL
Bone ___ results from intermittent exposure to PTH
Bone formation results from intermittent exposure to PTH
- Mechanisms: decreased osteoblast apoptosis, increased osteoblast differentiation, and suppression of sclerostin production
Teriparatide (PTH 1-34) is an ____ agent for the treatment of ____
Teriparatide (PTH 1-34) is an anabolic agent for the treatment of osteoporosis
- Administered by subcutaneous injection only daily
- Concerns: hypercalcemia, osteosarcoma (not seen in humans)
Parathyroid hormone related peptide ____, ____, and ____
Parathyroid hormone related peptide is an etiologic factor in the hypercalcemia of malignancy and in osteolytic metastases of breast cancer, effects on mammary glands / placenta / smooth muscle, and anabolic actions on bone
- Abaloparatide is PHTHrP analog
Calcitonin is secreted by ____ after stimulation by ____
Calcitonin is secreted by C-cells of thryoid gland after stimulation by calcium
Calcitonin acts on ____ through GPCRs to ____
Calcitonin acts on mature osteoclasts through GPCRs to inhibit bone resorption
- Antiresorptive
- Useful for Paget’s disease
Fibroblast growth factor 23 is produced by ____ and ____ and its synthesis is increased by ____ and ____
Fibroblast growth factor 23 is produced by osteoblasts and osteocytes and its synthesis is increased by calcitriol and phosphate
Fibroblast growth factor 23 functions to ___
Fibroblast growth factor 23 functions to inhibit renal calcitriol synthesis and phosphate reabsorption
Describe pathophysiology resulting from low/high FGF-23
Pathophysiology resulting from low/high FGF-23
- Tumoral calcinosis results from mutations that inhibit FGF 23 secretion
- Hypophosphatemic rickets result from mutations in a cleavage site required for FGF 23 inactivation
Estrogen is important for maintenance of ____
Estrogen is important for maintenance of bone
- Decreased estrogen at menopause accelerates bone loss
Estrogen is ____ and ____
Estrogen is antiresorptive and anabolic
- Inhibits production of RANKL and IL-6
- Increases production of osteoprotegerin
- Causes apoptosis of osteoclasts
- Decreases sclerostin, promoting bone formation
Androgens are aromatized to ____ in bone and act on ____
Androgens are aromatized to estrogen in bone and act onestrogen receptors
____ has been reported in males with aromatase deficiency or who lack estrogen receptors
Osteoporosis has been reported in males with aromatase deficiency or who lack estrogen receptors
Raloxifene is a ___
Raloxifene is a selective estrogen response modulator
Selective estrogen response modulators (raloxifene) interacts with ____
Selective estrogen response modulators (raloxifene) interacts with estrogen receptors in a tissue-specific manner
- Estrogenic actions on bone (largely antiresorptive)
- Anti-estrogenic effects on the mammary gland
Selective estrogen response modulators (raloxifene) are used to ____ and ____
Selective estrogen response modulators (raloxifene) are used to prevent / treat postmenopausal osteoporosis and reduce risk of breast cancer
- Adverse effects: thromboses (estrogenic), hot flashes (anti-estrogenic), contraindicated in women who may become pregnant
Alendronate, risedronate, zoledronic acid, and ibandronate are ____
Alendronate, risedronate, zoledronic acid, and ibandronate are bisphosphonates
- Analogs of pyrophosphate
Bisphosphonates ___ and ___
Bisphosphonates accumulate in bone at sites of active resorption and inhibit osteoclast activity and survival after being taken up
- Antiresorptive
- Alendronate, risedronate, zoledronic acid, ibandronate
Bisphosphonates are used to ____ and treat ____, ____, and ____
Bisphosphonates are used to prevent / treat osteoporosis and treat bone metastases from breast / prostate cancer, hypercalcemia, and Paget’s disease
Describe adverse effects of bisphosphonates
Adverse effects of bisphosphonates
- Heartburn, esophageal irritation, esophagitis
- Abdominal pain, diarrhea
- Osteonecrosis of the jaw and atypical femoral fractures are rare but serious
Denosumab is a ____ that ____ and ____
Denosumab is a human monoclonal antibody against RANKL that inhibits osteoclast fusion, function, and survival (antiresorptive) and increases bone mineral density and decreases fractures
- Used to treat osteoporosis
Describe adverse effects of denosumab
Denosumab adverse effects
- Hypocalcemia
- Rashes
- Osteonecrosis of jaw
- Risk of infections in individuals with weak immune system
Describe anti-resorptive therapy for osteoporosis
Anti-resorptive therapy for osteoporosis
Describe formation-stimulating (anabolic) therapy for osteoporosis
Formation-stimulating (anabolic) therapy for osteoporosis
___ and ___ are anabolic (bone formation) therapy for osteoporosis
PTH (teriparatide) and abaloparatide are anabolic (bone formation) therapy for osteoporosis
Short term glucocorticoid treatment can reduce ____ through ____ and ____
Short term glucocorticoid treatment can reduce hypercalcemia through decreased intestinal calcium absorption and increased renal calcium excretion
Chronic glucocorticoid treatment can cause ____
Chronic glucocorticoid treatment can cause osteoporosis
- Decreased intestinal Ca absorption
- Increase renal Ca excretion
- Increase PTH secretion
- Decrease gonadal steroids
- Decrease protein synthesis in bone
Hypocalcemia is treated with ____, ____, ____, and ____
Hypocalcemia is treated with Vitamin D, caclitriol, alphacalcidol, and thiazide diuretics
Hypercalcemia is treated with ____, ____, ____, and ____
Hypercalcemia is treated with loop diuretics, bisphosphonates, calcitonin, and glucocorticoids
Antiresorptive treatment for osteoporosis involves ____, ____, ____, ____, and ____
Antiresorptive treatment for osteoporosis involves bisphosphonates, denosumab, selective estrogen receptor modulators, estrogen, and calcitonin
(with Ca, Vitamin D, and exercise)
Anabolic treatment for osteoporosis involves ____ and ____
Anabolic treatment for osteoporosis involves teriparatide (PTH) and abaloparatide (PTHrP analog)
(Ca, Vitamin D, and exercise)
